The candidate is an Assistant Professor (tenure track) with primary clinical interest in Endocrine Surgical Oncology and training in basic science research. She is very committed to a long-term career goal of establishing herself as an independent investigator in the area of thyroid cancer research. She has been working in a very collaborative and synergistic environment with substantial institutional commitment to her academic success. She is applying for this award with the intent of eventually being able to apply for an NIH R01 grant and establish her own research program. Her career development plan for this award mechanism includes formal course work and attendance at seminars and conferences pertinent to her field of research with a goal to increase both didactic and practical knowledge in the mechanisms of gene regulation in cancers. In addition, she will interact closely with her mentors and Research Review Committee to ensure that she progresses to independence. Thyroid cancer is the most common malignancy affecting the endocrine glands and its incidence rates have been rising over the past 30 years. It is not a uniformly fatal malignancy. However, recurrent disease (occurring in 25% of patients) has been reported to increase subsequent mortality, even from well- differentiated thyroid cancers. Well-differentiated tumors are typically treated with surgery and radio-active iodine ablation. However, recurrences are often less responsive to radioactive iodine and it is not possible to reliably predict which tumors will recur or metastasize. In addition, some types of thyroid cancer such as anaplastic tumors are very aggressive and currently have no effective therapy. Preliminary studies suggest that Extracellular Matrix 1 (ECM1) is over-expressed in anaplastic thyroid cancers and that its expression may be a prognostic indicator in differentiated thyroid malignancies. Additional preliminary studies using cell line models indicate that TFAP2C likely regulates ECM1 expression. The hypothesis underlying the proposed work is that ECM1 is an important prognostic marker in thyroid cancer that confers increased metastatic potential and that its expression is regulated by TFAP2. This application proposes to expand our understanding of the regulation of ECM1 overexpression and its role in prognosis with the following specific aims. 1) Determine the mechanisms of transcriptional regulation of ECM1, with particular reference to TFAP2C;2) Examine the role of ECM1 over-expression and silencing on invasive and metastatic potential of tumor cells and 3) Examine the role of ECM1 expression as a determinant of outcome in patients with thyroid cancer and determine whether it is co-expressed with TFAP2C. Luciferase assays will be used to define the promoter region of ECM1 and chromatin immunoprecipitation will be used to determine if TFAP2C binds this region. The effects of ECM1 overexpression will be evaluated using in vitro invasion and migration assays and in vivo in an orthotopic mouse model. Lastly, ECM1 expression will be examined by real-time RT-PCR and immunohistochemistry in a hospital-based cohort of patients with thyroid cancer to determine whether it correlates with clinical outcomes. The significance and health-relatedness of this research endeavor is that it will increase our understanding of the molecular and genetic basis of the aggressive and poor-prognosis phenotype of thyroid cancer. This will hopefully lead to new insights regarding their development and enhance our ability to discover novel and directed therapies for these and other poor-risk tumors. PUBLIC HEALTH RELEVANCE: Thyroid cancer is the most common malignancy affecting the endocrine glands and thyroid cancer incidence rates have been rising over the last 30 years. Despite numerous classification systems, it is not possible to reliably predict which differentiated tumors will recur or metastasize and some types of thyroid cancer such as anaplastic tumors are very aggressive. Understanding the molecular and genetic basis of the aggressive and poor-prognosis phenotype of thyroid cancer will lead to new insights regarding the development and treatment of these tumors.